1-216365031-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_206933.4(USH2A):​c.706C>A​(p.Pro236Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P236H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.85
Variant links:
Genes affected
USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19254965).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH2ANM_206933.4 linkc.706C>A p.Pro236Thr missense_variant Exon 4 of 72 ENST00000307340.8 NP_996816.3 O75445-1
USH2ANM_007123.6 linkc.706C>A p.Pro236Thr missense_variant Exon 4 of 21 NP_009054.6 O75445-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.706C>A p.Pro236Thr missense_variant Exon 4 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000366942.3 linkc.706C>A p.Pro236Thr missense_variant Exon 4 of 21 1 ENSP00000355909.3 O75445-2
USH2AENST00000674083.1 linkc.706C>A p.Pro236Thr missense_variant Exon 4 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250978
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135636
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461430
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727022
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152126
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Usher syndrome type 2A Uncertain:2
Nov 11, 2019
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 04, 2023
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Oct 20, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Pro236Thr var iant in USH2A has not been previously reported in individuals with hearing loss, but has been identified in 1/66638 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs762558966). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The proline (Pro) at position 236 is not conserved in mammals or evolutionary distant species, raising the possibility th at a change at this position may be tolerated. Additional computational predicti on tools suggest that the p.Pro236Thr variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary , while the clinical significance of the p.Pro236Thr variant is uncertain, the a vailable data suggest that it is more likely to be benign. -

not provided Uncertain:1
Jul 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 236 of the USH2A protein (p.Pro236Thr). This variant is present in population databases (rs762558966, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 229626). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Retinitis pigmentosa 39 Uncertain:1
Nov 04, 2023
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1
Oct 01, 2023
Dept Of Ophthalmology, Nagoya University
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
14
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
T;.
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.19
T;T
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
1.4
L;L
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.11
Sift
Benign
0.11
T;T
Sift4G
Uncertain
0.028
D;T
Polyphen
0.18
B;P
Vest4
0.20
MutPred
0.38
Loss of phosphorylation at T235 (P = 0.0774);Loss of phosphorylation at T235 (P = 0.0774);
MVP
0.88
MPC
0.075
ClinPred
0.50
D
GERP RS
4.6
Varity_R
0.067
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs762558966; hg19: chr1-216538373; API